Cardiomyocyte hypertrophy increases the risk of adverse clinical events and is a common prelude to cardiac dilatation and heart failure. However, little is known about the counter-regulatory mechanisms controlling cardiomyocyte hypertrophy or the mechanisms mediating the transition to heart failure. [unreadable] Using microarray analysis of hypertrophic hearts from Akt transgenic mice, we have recently identified dramatic induction of myostatin, a highly conserved negative regulator of skeletal muscle growth, not previously known to play a role in the heart. Preliminary in vitro data suggest myostatin expression exerts a potent anti-hypertrophic effect in cardiomyocytes. However, the long-term effects of inhibiting cardiomyocyte hypertrophy in this way are unknown. The goals of the current proposal are to examine the role of myostatin in both in vitro and in vivo models of cardiac hypertrophy and failure. [unreadable] This proposal is based on three hypotheses: 1) that myostatin is an endogenous negative regulator of cardiac hypertrophy, 2) that cardiac myostatin activity is induced by cardiac hypertrophy in vivo, and that 3) myostatin expression ultimately contributes to the transition from hypertrophy to dilatation and heart failure by enhancing cardiomyocyte apoptosis. To test these hypotheses, we will study the effects of myostatin inhibition or deletion, as well as cardiac expression of myostatin, in both in vitro and in vivo models of cardiomyocyte hypertrophy, apoptosis, and failure. In Specific Aim 1, we will examine the effects of myostatin expression in vitro on cardiomyocyte hypertrophy and apoptosis. In Specific Aim 2, we will define the downstream signaling pathways involved. In Specific Aim 3, we will evaluate the long-term effects of myostatin deletion on the heart both at baseline and in models of cardiac hypertrophy and failure in vivo. In Specific Aim 4, we will examine the effects of transgenic cardiac expression of myostatin or the inhibitory myostatin propeptide, at baseline and in models of cardiac hypertrophy. [unreadable] Understanding the role of specific pathways in cardiomyocyte hypertrophy may provide novel therapeutic approaches for the management of cardiac hypertrophy and heart failure. [unreadable] [unreadable]